Human Molecular Genetics, 2002, Vol. 11, No. 24 3107-3114
© 2002 Oxford University Press
Rescue of neurodegeneration in Niemann–Pick C mice by a prion-promoter-driven Npc1 cDNA transgene
1National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, 2Angel Charity for Children—Wings for Genetic Research, Steele Memorial Children's Research Center, Department of Pediatrics, University of Arizona, Tucson, AZ, USA, 3Department of Molecular and Cellular Biology and Genetics Committee, University of Arizona, Tucson, AZ, USA, 4Sidney Weisner Laboratory of Genetic Neurological Disease, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA and 5Diagnostic and Research Services Branch, Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
Received August 19, 2002; Accepted September 23, 2002
Niemann–Pick disease type C (NPC) is a neurodegenerative disorder with major visceral complications, including liver disease that can be fatal before onset of neurodegeneration. We have sought to determine the extent to which visceral disease contributes to neurodegeneration by making transgenic mice in which the wild-type NPC1 protein is expressed primarily in the CNS using the prion promoter. When the transgene was introduced into the npc1-/- animals neurodegeneration was prevented, a ‘normal’ lifespan occurred and the sterility of npc1-/- mice was corrected. The rescue did not provide complete neurological correction in the CNS as GM2 and GM3 gangliosides were observed to accumulate in some neurons and glia of transgenic animals. Two of three transgenic lines demonstrated some low-level ectopic expression resulting in correction of visceral phenotypes in liver and spleen. Interestingly, the third transgenic line continued to have moderate histocytosis in liver and spleen, yet had no detectable neurodegeneration. Thus, it is primarily the lack of NPC1 in the CNS and not the secondary effects of the visceral involvement that causes the neurological decline in NPC disease. In addition, the expression levels of NPC1 found in the CNS of transgenic animals were much greater than in normal littermates, demonstrating that overexpression of NPC1 is not harmful and allowing possibilities for genetic therapy interventions that utilize overexpression.
* To whom correspondence should be addressed at: National Institutes of Health, National Human Genome Research Institute, Genetic Disease Research Branch, 49 Convent Dr., Building 49, Room 4A67, Bethesda, MD 20892, USA. Tel: +1 3014967584; Email: bpavan{at}nhgri.nih.gov
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